Urinary transcription factor 21 (TCF21) as a non-invasive biomarker of podocyte injury in preeclampsia: diagnostic performance and translational insights from a case-control study.

BACKGROUND: Early detection of preeclampsia may reduce maternal and fetal morbidity and mortality. While angiogenic biomarkers (sFlt-1 and PlGF) are clinically useful, their sensitivity is imperfect. Podocyte injury is implicated in preeclampsia; urinary transcription factor 21 (TCF21) may serve as a non-invasive marker of glomerular involvement. METHODS: In this case-control study, 160 women with preeclampsia and 64 normotensive pregnant controls matched for age and gestational age were enrolled to evaluate the diagnostic utility of urinary TCF21 and its performance alongside angiogenic markers (sFlt-1, PlGF) at the time of clinical presentation for suspected preeclampsia. Preeclampsia cases were stratified into mild (n = 92) and severe (n = 68) disease, and each group was further stratified into early-onset and late-onset preeclampsia. Biomarker performance was assessed using logistic regression, receiver operating characteristic (ROC) analysis, and multivariable modeling. RESULTS: Compared with controls, women with preeclampsia had higher sFlt-1 (11.4-fold; p < 0.001), a higher sFlt-1/PlGF ratio (40.6-fold; p < 0.001), and higher urinary TCF21 (1.7-fold; p < 0.001), with lower PlGF (− 68%; p < 0.001). Urinary TCF21 demonstrated moderate discrimination for preeclampsia (AUC 0.769) and was inferior to the sFlt-1/PlGF ratio (AUC 0.812). At the prespecified cutoff of > 370 pg/mL, urinary TCF21 achieved 60.6% sensitivity and 90.6% specificity (LR + 6.45; LR − 0.43). Urinary TCF21 showed an exploratory inverse association with severity (r = − 0.258, p < 0.001) and diastolic blood pressure (r = − 0.244, p = 0.002). In multivariable analysis, urinary TCF21 remained independently associated with preeclampsia (adjusted odds ratio 2.83 per 50 pg/mL; 95% CI 1.49–5.59; p = 0.002), and combined models improved discrimination (AUC 0.87; 95% CI 0.82–0.91). CONCLUSIONS: Urinary TCF21 is a novel, non-invasive biomarker associated with preeclampsia and showed a hypothesis-generating inverse association with disease severity. In this case-control cohort, its high specificity suggests potential adjunct confirmatory performance at presentation when interpreted alongside angiogenic testing; however, cutoffs and probability thresholds are exploratory and require prospective external validation. Future studies should include creatinine-normalized reporting, assay standardization, and longitudinal sampling to evaluate predictive utility prior to symptom onset.